Many methods exist to nondestructively measure the composition of materials. For materials such as living tissue, x-ray is the oldest method of measurement. Differences in x-ray absorption result from differences in atomic number and differences in density. These differences can be measured by capturing a transmitted x-ray flux on a photographic medium or with an equivalent electronic detector, as in an x-ray computed tomographic scanner. Contrast agents can be introduced, typically with high atomic numbers such as iodine, to enhance features in the tissue. Nuclear tracers and radiopharmaceuticals can be introduced and detected by their emission of typically gamma radiation.
Ultrasound measures acoustic impedance. Sound waves are reflected from boundaries between tissues of differing acoustic impedances, allowing reconstruction of image data from the acoustic signals.
Magnetic resonance imaging detects the presence and chemical composition of certain atoms such as hydrogen and phosphorus in the tissue. Tracer compounds can be introduced, typically with high paramagnetism (e.g. gadolinium), to enhance features in the tissue.
In recent times, the use of light and more specifically laser light to noninvasively reveal the interior structure of the body has been investigated. Optical techniques inject light of one or more wavelengths at one or more locations into tissue and detect light emitted from that tissue at one or more locations.
Continuous wave (CW) optical measurement, employing continuous, unmodulated light, can measure overall light absorption, which is a combination of scattering and attenuation in the tissue. Time-resolved optical measurement, employing very brief light pulses, can distinguish the scattering from attenuation, thus presenting more information regarding the medium being measured. Similarly, frequency domain optical measurements employ light that is modulated at a high frequency, and by measuring the phase and amplitude of the received light, can distinguish the scattering from attenuation.
The scientific paper “Time resolved reflectance and transmittance for the noninvasive measurement of tissue properties”, by Patterson, Chance and Wilson, Applied Optics, Vol. 28 No. 12, 15 Jun. 1989, develops analytic models from the diffusion equation approximation to the radiative transfer theory. From these models, for a semi-infinite slab of tissue (a good approximation for any relatively large body part), the effective transport scattering coefficient μs′ (which is (1−g)μs from this paper) and the absorption coefficient μa, can be determined from the shape, duration, and amplitude of the temporal point spread function (TPSF). The approximate double-exponential shape of the TPSF results from the varying number of scattering events each photon encounters while traversing a turbid medium, such as biological tissue. The first photons received presumably have experienced relatively few scattering events, and therefore must have taken the most direct paths from the laser source to the detector probe. The later photons have traveled more circuitous paths through the medium. The early photons may be used to improve the resolution of some optical imaging techniques, especially those derived from x-ray imaging, because the photons' trajectories begin to resemble rays.
The diffusion approximation to the radiative transport equation is given by:
            α      ⁢                        ∂          Φ                          ∂          t                      -                  ∇        2            ⁢      Φ        +          β      ⁢                          ⁢      Φ        =  0
A solution to the diffusion equation for an infinite slab is given by:
            Φ      ⁢                          ⁢              (                  t          ,          d                )              =                  1                  t                      3            /            2                              ⁢              ⅇ                              -            α                    ⁢                                    d              2                                      4              ⁢              t                                          ⁢              ⅇ                              -                          (                              β                /                α                            )                                ⁢                                          ⁢          t                                        where        ⁢                  :                ⁢                                  ⁢        α            =                        3          ⁢                                          ⁢                      (                                          μ                a                            +                              μ                s                ′                                      )                          nc              ,                  ⁢          β      =              3        ⁢                              μ            a                    ⁡                      (                                          μ                a                            +                              μ                s                ′                                      )                                ,                  d is the tissue thickness,        μa is the absorption coefficient,        μs′ is the effective transport scattering coefficient,        n is the index of refraction, and        c is the speed of light.        
FIG. 1 illustrates TPSFs for path lengths of 1.0, 10.0, and 20.0 cm generated using the above solution for the diffusion equation. The optical properties for these simulations were set to μa=0.006/mm, μa′=0.1/mm and n (index of refraction)=1.33, approximating the bulk tissue optical properties of human breast tissue (see J. Swartling, A. Pifferi, F, Chikoidze, A. Torricelli, P. Taroni, R. Cubeddu, and S. Andersson-Fngels, “Diffuse time-resolved reflectance and transmittance measurements of the female breast using different interfiber distances in the region 610-1040 nm,” in Biomedical Topical Meetings on CD-ROM (The Optical Society of America, Washington, D.C., 2004), WF17.) From FIG. 1, the TPSF widths range from less than 2 to more than 8 nanoseconds for path lengths of 1 to 20 cm in human breast tissue.
U.S. Pat. No. 6,339,216 employs a narrow-pulsed mode-locked Ti-Sapphire laser with an analog time-gating circuit to measure both the shape and amplitude of the light signal (the TPSF) emanating from the breast. A single time gate samples each TPSF and is moved across successive TSPFs in order to acquire the entire shape of the pulse, in the fashion of oscilloscope sampling units. The disadvantage of this approach is that if 50 samples are required across the TPSF to adequately characterize it, then 50 TPSFs must be sampled. This approach is fundamentally inefficient.
International Patent Publication WO 2003/009229 A3 extends the concept of a single time gate to multiple gates, in order to collect more information about the TSPF in less total time, therefore shortening the time of an acquisition. This approach is marginally more efficient than that of U.S. Pat. No. 6,339,216, shortening the measurement time by 2× or 3× practically. A dramatic reduction in acquisition times, 10× or 20×, requires the number of fibers all precisely cut to differing lengths.
U.S. Pat. No. 5,386,827 employs a similar analog time-gating circuit for in vivo tissue spectroscopy.
U.S. Pat. No. 5,371,368 employs an optical Kerr cell gate to sample the TPSF, in the fashion of a sampling oscilloscope. The disadvantage of this approach is that if 20 samples are required across the TPSF to adequately characterize it, then 20 TPSFs must be sampled. This approach is fundamentally inefficient.
U.S. Pat. Nos. 5,752,519; 5,555,885; 5,119,815 and 5,148,031 employ time-flight technique to measure the TPSF. This is also referred to as “time-correlated single-photon counting”, where the arrival time of each photon is measured with respect to the emission time of the light pulse, usually using a Time-to-Amplitude Converter feeding a MultiChannel Analyzer. Assuming that less than 1 photon arrives per light pulse (a requirement), the histogram of those arrival times will be the shape of the TPSF. This has the disadvantage of being very slow. Thousands of light pulses are required to form a histogram with an acceptable signal-to-noise ratio.
U.S. Pat. No. 4,972,423 employs a streak camera to acquire the TPSF with a very high temporal resolution of 2 picoseconds. The disadvantage of this approach is the extremely high cost and fragility of streak cameras, limiting this approach to laboratory conditions.